The occurrence of fungal infections has escalated significantly in recent years and is expected to continue to increase for the foreseeable future. Unfortunately, only a limited number of antifungal drugs are currently available for use, due in part to a dearth of suitable targets. In this context, the ultimate aim of the proposed investigation is to test the premise that two-component histidine kinases (HK) will be useful targets for the detection of novel antifungal agents. HKs are attractive for this purpose since they are unique to lower eukaryotes and prokaryotes. Furthermore, the lack of a mammalian counterpart increases the likelihood of identifying an efficacious agent. we have chosen to examine this issue in Candida albicans, since it is the most common fungal pathogen in humans. More important, we-have already isolated and sequenced one histidine kinase gene (CaHK1) and have recently isolated a second (CaHK2). This work will now be extended to include: l. Validation of HKs as targets in the mouse model of systemic candidiasis. 2. Development of high throughput assays for CaHK1 and CaHK2 activities. 3. Preliminary screening of natural products for activity against the HKs. PROPOSED COMMERCIAL APPLICATIONS: Successful identification of new chemotherapeutic agents for the treatment of deep-seated fungal infections would have a major impact on the physician's ability to effectively care for patients suffering from systemic mycosis.